L596-W733 bond between the start of the S4-S5 linker and the TRP box stabilizes the closed state of TRPV4 channel

Proceedings of the National Academy of Sciences of the United States of America
Jinfeng TengChing Kung

Abstract

Unlike other cation channels, each subunit of most transient receptor potential (TRP) channels has an additional TRP-domain helix with an invariant tryptophan immediately trailing the gate-bearing S6. Recent cryo-electron microscopy of TRP vanilloid subfamily, member 1 structures revealed that this domain is a five-turn amphipathic helix, and the invariant tryptophan forms a bond with the beginning of the four-turn S4-S5 linker helix. By homology modeling, we identified the corresponding L596-W733 bond in TRP vanilloid subfamily, member 4 (TRPV4). The L596P mutation blocks bone development in Kozlowski-type spondylometaphyseal dysplasia in human. Our previous screen also isolated W733R as a strong gain-of-function (GOF) mutation that suppresses growth when the W733R channel is expressed in yeast. We show that, when expressed in Xenopus oocytes, TRPV4 with the L596P or W733R mutation displays normal depolarization-induced activation and outward rectification. However, these mutant channels have higher basal open probabilities and limited responses to the agonist GSK1016790A, explaining their biological GOF phenotypes. In addition, W733R current fails to inactivate during depolarization. Systematic replacement of W733 with amino ...Continue Reading

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Citations

Sep 22, 2015·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Monique S J Brewster, Rachelle Gaudet
Apr 14, 2016·Proceedings of the National Academy of Sciences of the United States of America·Mahmud Arif PavelYong Yu
Aug 6, 2015·Biophysical Journal·Lucia Gregorio-TeruelAntonio Ferrer-Montiel
Apr 30, 2015·Biochimica Et Biophysica Acta·A R BattleB Martinac
Mar 16, 2017·The Journal of Physiology·Trine L Toft-BertelsenNanna MacAulay
Oct 26, 2018·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Robin WrayPaul Blount
Jun 3, 2016·Physiological Reviews·John P M WhiteIstvan Nagy
Oct 4, 2017·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Wang ZhengXing-Zhen Chen
Jul 19, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Wenying XianPeter Lipp
Nov 24, 2016·Frontiers in Physiology·Geunyeol Choi, Sun Wook Hwang
Oct 30, 2016·Proceedings of the National Academy of Sciences of the United States of America·Jinfeng TengChing Kung
Apr 24, 2019·Proceedings of the National Academy of Sciences of the United States of America·Jinfeng TengPaul Blount
Aug 24, 2020·IScience·Ruiqi CaiJingfeng Tang
Jun 26, 2021·Nature Structural & Molecular Biology·Zheng RuanWei Lü

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